This review deliberates whether SARS-CoV-2 can access the central nervous system (CNS) and contribute to acute respiratory distress.
Study design
The authors evaluated the epidemiologic and overlapping clinical features of SARS-CoV, MERS-CoV, HEV 67N, Avian Bronchitis Virus and SARS-CoV-2, paying attention to this family of virus’ potential to infect the brain. The authors correlated clinical features with neuroanatomical substrates and suggest evidence for the presence of viral particles concentrated in various brain regions.
Outcomes
This is a fascinating paper describing the presence of viral particles in the brain of patients with SARS-CoV infection in 2003. Given the high sequence homology and overlapping clinical pictures between SARS-CoV-2 and other coronavirus infections, the authors postulate the potential importance of CNS localization of some clinical symptoms and signs. In particular, acute respiratory distress syndrome is widely recognized in both diseases, and was found in SARS-CoV patients with a high concentration of viral particles in the cardiorespiratory center in the brainstem.
Experimental studies in mice infected with SARS-CoV and MERS-CoV demonstrate that viral particles can enter the brain through the olfactory nerve terminals and gain access to various upper and lower brainstem structures. It is well known that some patients infected with SARS-CoV-2 report gustatory and olfactory dysfunction early in the course of disease. It seems plausible that this early clinical finding may represent initial infection within the olfactory system, followed by respiratory distress correlating with the migration of the viral infection transneuronally to the distal cardiorespiratory brainstem structures within the medulla over the subsequent days.
Although the direct mechanism is unknown, direct transsynaptic transfer of virus particles is more likely than hematogenous or lymphatic transmission since the vast majority of avian influenza viral particles were found in neurons, not the surrounding nonneuronal structures. Based on HEV 67N data, the authors also propose retrograde transfer from peripheral nerve terminals within the lungs to the medullary neurons as a possible mechanism. Nuclei of the solitary tract and nucleus ambiguus connect with the mechano- and chemoreceptors of the lung, which is the basis for the proposed neural circuitry and clinical findings.
Limitations
This study lacks the autopsy evidence of deceased SARS-CoV-2 patients which might confirm or refute these hypotheses. At this point, the theories presented are based on the molecular, biological and clinical overlap between known coronavirus diseases and extrapolated to COVID-19. Noninvasive imaging has not been used to determine whether a patient’s respiratory issues localize, at least in part, to the CNS. Since hospitals are currently overwhelmed, facilities will not be able to deploy novel structural or functional imaging studies to determine this. Autopsy studies may help shed further light on this phenomenon.
Clinical significance
It is extremely important to recognize that patients experiencing respiratory distress may have a neurological control aspect in addition to pulmonary infection and damage. Drugs that can cross the blood-brain barrier (BBB) may be necessary if a brainstem concentration of infection is confirmed. P-glycoprotein is among a group of proteins thought to be important in maintaining the BBB. Inhibitors of this protein have gained interest as potential adjuvants to chemotherapy for brain tumors because they may produce temporary BBB permeability to allow neuro-oncologic agents into the CNS. Similarly, if a potentially therapeutic antiviral agent is identified with efficacy against SARS-CoV-2, reaching its CNS target may be very relevant and could be facilitated using the same approach.